DIFFICULT-TO-TREAT & SEVERE ASTHMA

Transcription

1 GOBA INITIATIVE FOR ASTHMA GINA DIFFICUT-TO-TREAT & SEVERE ASTHMA in adolescent and adult patients Diagsis and Management A GINA Pocket Guide For Health Professionals November 2018 Global Initiative for Asthma,

2 GINA DIFFICUT-TO-TREAT & SEVERE ASTHMA in adolescent and adult patients Diagsis and Management A GINA Pocket Guide For Health Professionals November 2018 Global Initiative for Asthma,

3 Abbreviations used in this Pocket Guide Table of Contents +++, ++, +: Plus signs indicate the strength of an association ABPA: Allergic bronchopulmonary aspergillosis AERD: Aspirin-exacerbated respiratory disease ANCA: Antineutrophil cytoplasmic antibody BNP: B-type natriuretic peptide CBC: Complete blood count COPD: Chronic obstructive pulmonary disease CRP: C-reactive protein CT/HRCT: Computerized tomography; high resolution computerized tomography CXR: Chest X-ray DPI: Dry powder inhaler DCO: Diffusing capacity in the lung for carbon moxide FeNO: Fraction of exhaled nitric oxide FEV 1 : Forced expiratory volume in 1 second FVC: Forced vital capacity GERD: Gastro-esophageal reflux disease GP: General practitioner; primary care physician ICS: Inhaled corticosteroids Ig: Immuglobulin I: Interleukin IM: Intramuscular IV: Intraveus : Check local eligibility criteria for specific biologic therapies as these may vary from those listed ABA: ong-acting beta2-agonist M/TRA: eukotriene modifier/leukotriene receptor antagonist NSAID: Non-steroidal anti-inflammatory drug OCS: Oral corticosteroids OSA: Obstructive sleep apnea pmdi: Pressurized metered dose inhaler RCT: Randomized controlled trial SABA: Short-acting beta2-agonists SC: Subcutaneous VCD: Vocal cord dysfunction Abbreviations used in this Pocket Guide...2 Goal of this Pocket Guide... 4 How to use this Pocket Guide... 5 Definitions: uncontrolled, difficult-to-treat and severe asthma...6 Prevalence: how many people have severe asthma? Importance: the impact of severe asthma...7 Severe asthma decision tree: diagsis and management...8 Investigate and manage adult and adolescent patients with difficult-to-treat asthma GP OR SPECIAIST CARE Decision Detail Tree Pages 1 Confirm the diagsis (asthma or differential diagses) ook for factors contributing to symptoms, exacerbations and poor quality of life Optimize management Review response after ~3-6 months Assess and treat severe asthma phetypes SPECIAIST CARE; SEVERE ASTHMA CINIC IF AVAIABE 5 Assess the severe asthma phetype and factors contributing to symptoms, quality of life and exacerbations a Consider n-biologic treatments b Consider add-on biologic Type 2 targeted treatments Monitor / Manage severe asthma treatment SPECIAIST AND PRIMARY CARE IN COABORATION 7 Review response Continue to optimize management as in section Glossary of asthma medication classes Ackwledgements, GINA publications, other resources for severe asthma...31 References Adolescents and adults with difficult-to-treat and severe asthma GINA Adolescents and adults with difficult-to-treat and severe asthma GINA

4 Goal of this Pocket Guide How to use this Pocket Guide The goal of this Pocket Guide is to provide a practical summary for health professionals about how to identify, assess and manage difficult-to-treat and severe asthma in adolescents and adults. It is intended for use by general practitioners (GPs, primary care physicians), pulmonary specialists and other health professionals involved in the management of people with asthma. More details and practical tools for asthma management in clinical practice, particularly for primary care, can be found in the GINA 2018 strategy report and appendix and the online GINA toolbox, available from How was the Pocket Guide developed? The recommendations in this Pocket Guide were based on evidence where good quality systematic reviews or randomized controlled trials or, lacking these, robust observational data, were available, and on consensus by expert clinicians and researchers, where t. Development of the Pocket Guide and decision tree included extensive collaboration with experts in human-centered design to enhance the utility of these resources for end-users. This means translating existing high level flowcharts and text-based information to a more detailed visual format, and applying information architecture and diagramming principles. This GINA Pocket Guide is intended as a practical guide for health professionals about the assessment and management of difficult-to-treat and severe asthma. It does NOT contain all of the information required for managing asthma. The Pocket Guide should be used in conjunction with the full GINA 2018 report. Health professionals should also use their own clinical judgment and take into account any local restrictions or payer requirements. GINA cant be held liable or responsible for inappropriate healthcare associated with the use of this document, including any use which is t in accordance with applicable local or national regulations or guidelines. The Table of Contents (page 3) summarizes the overall steps involved in assessing and treating an adult or adolescent who presents with difficult-to-treat asthma (see definitions on page 6). A clinical decision tree is found on pages 8 to 15, providing brief information about what should be considered in each phase. The decision tree is divided into three broad areas: Sections 1-4 (green) are for use in primary care and/or specialist care Sections 5-7 (blue) are mainly relevant to respiratory specialists Section 8 (brown) is about maintaining ongoing collaborative care between the patient, GP, specialist and other health professionals Circles indicate diagsis Key section of the decision tree, numbered GP OR SPECIAIST CARE Key decision, filters intervention, treatment diagsis, confirmation Page number for more details Investigate and manage adult and adolescent patients with Consider referring to specialist or severe asthma clinic at any stage DIAGNOSIS: Difficultto-treat asthma For adults and adolescents with symptoms and/or exacerbations despite GINA Step 4 treatment, or taking maintenance OCS ocus of care: GP or specialist 1 Confirm the diagsis (asthma/differential diagses) 2 ook for factors contributing to symptoms, exacerbations and poor quality of life: Incorrect inhaler technique Suboptimal adherence Comorbidities including obesity, GERD, chronic rhisinusitis, OSA Modifiable risk factors and triggers at home or work, including smoking, environmental exposures, allergen exposure (if sensitized on skin prick testing or specific IgE; medications such as beta-blockers and NSAIDs) Overuse of SABA relievers Medication side effects Anxiety, depression and social difficulties 3 Optimize management, including: Asthma education Optimize treatment (e.g. check and correct inhaler technique and adherence; switch to ICS-formoterol maintenance and reliever therapy, if available) Treat comorbidities and modifiable risk factors Consider n-biologic add-on therapy (e.g. ABA, tiotropium, M/TRA, if t used) Consider n-pharmacological interventions (e.g. smoking cessation, exercise, weight loss, mucus clearance, influenza vaccination) Consider trial of high dose ICS, if t used Overall aim of the sections on this double page difficult-to-treat asthma For more details à p.99 à p.99 à p.99 Consider referring to specialist or severe asthma clinic at any stage 4 Review response after ~3-6 months Is asthma still uncontrolled? Consider stepping down treatment, OCS first (if used.) Does asthma become uncontrolled when treatment is stepped down? Continue optimizing management yes yes Reminders about ongoing issues DIAGNOSIS: Severe asthma Restore previous dose If t done by w, refer to a specialist, if possible. Diamonds indicate decision points Colored boxes indicate treatment More detailed information about each of the numbered sections of the decision tree follows on pages 16 to 27. Key references and additional resources are found at the end of the Pocket Guide, starting on page 28. Clicking on page/section numbers and citation numbers will take you to the relevant location in the Pocket Guide. 4 Adolescents and adults with difficult-to-treat and severe asthma GINA Adolescents and adults with difficult-to-treat and severe asthma GINA

5 Definitions: uncontrolled, difficult-to-treat and severe asthma Importance: the impact of severe asthma Understanding the definitions of difficult-to-treat and severe asthma starts with the concept of uncontrolled asthma. Uncontrolled asthma includes one or both of the following: Poor symptom control (frequent symptoms or reliever use, activity limited by asthma, night waking due to asthma) Frequent exacerbations ( 2/year) requiring oral corticosteroids (OCS), or serious exacerbations ( 1/year) requiring hospitalization Difficult-to-treat asthma 1 is asthma that is uncontrolled despite GINA Step 4 or 5 treatment (e.g. medium or high dose inhaled corticosteroids (ICS) with a second controller; maintenance OCS), or that requires such treatment to maintain good symptom control and reduce the risk of exacerbations. It does t mean a difficult patient. In many cases, asthma may appear to be difficult-to-treat because of modifiable factors such as incorrect inhaler technique, poor adherence, smoking or comorbidities, or because the diagsis is incorrect. Severe asthma 1 is a subset of difficult-to-treat asthma (Box 1). It means asthma that is uncontrolled despite adherence with maximal optimized therapy and treatment of contributory factors, or that worsens when high dose treatment is decreased. 1 At present, therefore, severe asthma is a retrospective label. It is sometimes called severe refractory asthma 1 since it is defined by being relatively refractory to high dose inhaled therapy. However, with the advent of biologic therapies, the word refractory is longer appropriate. Asthma is t classified as severe if it markedly improves when contributory factors such as inhaler technique and adherence are addressed. 1 Prevalence: how many people have severe asthma? Box 1. What proportion of adults have difficult-to-treat or severe asthma? 24% GINA Step 4-5 treatment 17% difficult-to-treat asthma = GINA Step 4-5 treatment + poor symptom control 3.7% severe asthma = GINA Step 4-5 treatment + poor symptom control + good adherence and inhaler technique These data are from a Dutch population survey of people 18 years with asthma 2 The patient perspective Patients with severe asthma experience a heavy burden of symptoms, exacerbations and medication side-effects. Frequent shortness of breath, wheeze, chest tightness and cough interfere with day-to-day living, sleeping, and physical activity, and patients often have frightening or unpredictable exacerbations (also called attacks or severe flare-ups). Medication side-effects are particularly common and problematic with OCS, 3 which in the past were a mainstay of treatment for severe asthma. Adverse effects of long-term OCS include obesity, diabetes, osteoporosis, cataracts diabetes, hypertension and adrenal suppression; psychological side-effects such as depression and anxiety are particularly concerning for patients. 4 Even shortterm use of OCS is associated with sleep disturbance, and increased risk of infection, fracture and thromboembolism. 5 Strategies to minimize need for OCS are therefore a high priority. Severe asthma often interferes with family, social and working life, limits career choices and vacation options, and affects emotional and mental health. Patients with severe asthma often feel alone and misunderstood, as their experience is so different from that of most people with asthma. 4 Adolescents with severe asthma The teenage years are a time of great psychological and physiological development which can impact on asthma management. It is vital to ensure that the young person has a good understanding of their condition and treatment and appropriate kwledge to enable supported self-management. The process of transition from pediatric to adult care should help support the young person in gaining greater automy and responsibility for their own health and wellbeing. Healthcare utilization and costs Severe asthma has very high healthcare costs due to medications, physician visits, hospitalizations, and the costs of OCS side-effects. In a UK study, healthcare costs per patient were higher than for type 2 diabetes, stroke, or chronic obstructive pulmonary disease (COPD). 6 In a Canadian study, severe uncontrolled asthma was estimated to account for more than 60% of asthma costs. 7 Patients with severe asthma and their families also bear a significant financial burden, t only for medical care and medications, but also through lost earnings and career choices. 6 Adolescents and adults with difficult-to-treat and severe asthma GINA Adolescents and adults with difficult-to-treat and severe asthma GINA

6 Severe asthma decision tree: diagsis and management GP OR SPECIAIST CARE Investigate and manage adult and adolescent patients with difficult-to-treat asthma Consider referring to specialist or severe asthma clinic at any stage Consider referring to specialist or severe asthma clinic at any stage DIAGNOSIS: Difficultto-treat asthma For adolescents and adults with symptoms and/or exacerbations despite GINA Step 4 treatment, or taking maintenance OCS Key decision, filters 1 Confirm the diagsis (asthma/differential diagses) 2 ook for factors contributing to symptoms, exacerbations and poor quality of life: Incorrect inhaler technique Suboptimal adherence Comorbidities including obesity, GERD, chronic rhisinusitis, OSA Modifiable risk factors and triggers at home or work, including smoking, environmental exposures, allergen exposure (if sensitized on skin prick testing or specific IgE); medications such as beta-blockers and NSAIDs Overuse of SABA relievers Medication side effects Anxiety, depression and social difficulties 3 Optimize management, including: Asthma education Optimize treatment (e.g. check and correct inhaler technique and adherence; switch to ICS-formoterol maintenance and reliever therapy, if available) Treat comorbidities and modifiable risk factors Consider n-biologic add-on therapy (e.g. ABA, tiotropium, M/TRA, if t used) Consider n-pharmacological interventions (e.g. smoking cessation, exercise, weight loss, mucus clearance, influenza vaccination) Consider trial of high dose ICS, if t used 4 Review response after ~3-6 months Is asthma still uncontrolled? Consider stepping down treatment, OCS first (if used.) Does asthma become uncontrolled when treatment is stepped down? yes yes DIAGNOSIS: Severe asthma Restore previous dose If t done by w, refer to a specialist, if possible. intervention, treatment Continue optimizing management diagsis, confirmation For more details g pg 16~17 g pg 18 g pg 19 8 Adolescents and adults with difficult-to-treat and severe asthma GINA Adolescents and adults with difficult-to-treat and severe asthma GINA

7 SPECIAIST CARE; SEVERE ASTHMA CINIC IF AVAIABE Assess and treat severe asthma phetypes Continue to optimize management as in section 3 (including inhaler technique, adherence, comorbidities) 5 Assess the severe asthma phetype and factors contributing to symptoms, quality of life and exacerbations Assess the severe asthma phetype during high dose ICS treatment (or lowest possible dose of OCS) Type 2 inflammation Is patient likely to have residual Type 2 airway inflammation? Note: these are t the criteria for add-on biologic therapy (see 6b) Blood eosiphils 150/µl and/or FeNO 20 ppb and/or Sputum eosiphils 2%, and/or Asthma is clinically allergen-driven (Repeat blood eosiphils and FeNO up to 3x, on lowest possible OCS dose) Investigate for comorbidities/differential diagses and treat/refer as appropriate - Consider: CBC, CRP, IgG, IgA, IgM, IgE, fungal precipitins; CXR and/or HRCT chest; DCO - Skin prick testing or specific IgE for relevant allergens, if t already done - Other directed testing (e.g. ANCA, CT sinuses, BNP, echocardiogram) based on clinical suspicion Consider need for social/psychological support Involve multidisciplinary team care (if available) Invite patient to enroll in registry (if available) or clinical trial (if appropriate) For more details g pg Adolescents and adults with difficult-to-treat and severe asthma GINA yes 6a Consider n-biologic treatments Consider adherence tests Consider increasing the ICS dose for 3-6 months Consider AERD, ABPA, chronic rhisinusitis, nasal polyposis, atopic dermatitis (clinical Type 2 phetypes with specific add-on treatment) Is add-on Type 2 biologic therapy available/ affordable? yes If add-on Type 2 biologic therapy is NOT available/affordable Consider higher dose ICS, if t used Consider n-biologic add-on therapy (e.g. ABA, tiotropium, M/TRA, macrolide*) Consider add-on low dose OCS, but implement strategies to minimize side-effects Stop ineffective add-on therapies If evidence of Type 2 inflammation: Review the basics: differential diagsis, inhaler technique, adherence, comorbidities, side-effects Avoid exposures (tobacco smoke, allergens, irritants) Consider investigations (if available and t done) - Sputum induction - High resolution chest CT - Bronchoscopy for alternative/additional diagses Consider add-on treatments - Trial of tiotropium or macrolide* (if t already tried) Not currently - Consider add-on low dose OCS, but implement eligible for biologics strategies to minimize side-effects - Stop ineffective add-on therapies Consider bronchial thermoplasty (+ registry) *Off-label g pg 22 Adolescents and adults with difficult-to-treat and severe asthma GINA

8 SPECIAIST CARE; SEVERE ASTHMA CINIC IF AVAIABE Assess and treat severe asthma phetypes cont d Continue to optimize management as in section 3 (including inhaler technique, adherence, comorbidities) 6b Consider add-on biologic Type 2 targeted treatments Consider add-on Type 2-targeted biologic for patients with exacerbations and allergic/eosiphilic biomarkers on high dose ICS-ABA, with/without daily OCS Consider local payer eligibility criteria and predictors of response when choosing between available therapies Also consider cost, dosing frequency, route (SC or IV), patient preference Which biologic is appropriate to start first? Anti-IgE Is the patient eligible for anti-ige (for severe allergic asthma)? Sensitization on skin prick testing or specific IgE Total serum IgE and weight within dosage range Exacerbations in last year Anti-I5 / Anti-I5R Is the patient eligible for anti-i5 / anti-i5r (for severe eosiphilic asthma)? Exacerbations in last year Blood eosiphils 300/µl What factors may predict good response to anti-ige? Blood eosiphils 260/µl ++ FeNO 20 ppb + Allergen-driven symptoms + Childhood-onset asthma + What factors may predict good response to anti-i5/5r? Higher blood eosiphils +++ More exacerbations in previous year +++ If eligible, trial of omalizumab for 4 months If eligible, trial of anti-i5 or anti-i5r for 4 months Good response? STOP add-on Good response? yes Consider switching to a different Type 2-targeted therapy, if eligible yes Good response to T2-targeted therapy Adult-onset of asthma ++ Check local eligibility criteria for specific biologic therapies as these may vary from those listed Eligible for neither? Return to section 6a Nasal polyposis ++ STOP add-on Consider switching to a different Type 2-targeted therapy, if eligible ittle/ response to T2-targeted therapy For more details g pg 23~25 12 Adolescents and adults with difficult-to-treat and severe asthma GINA Adolescents and adults with difficult-to-treat and severe asthma GINA

9 SPECIAIST AND PRIMARY CARE IN COABORATION Monitor / Manage severe asthma treatment Continue to optimize management yes 7 Review response Symptoms Exacerbations ung function Treatment intensity Side-effects Affordability Patient satisfaction If good response to Type 2-targeted therapy Re-evaluate ongoing therapy every 3-6 months For oral treatments: consider decreasing/stopping OCS first, then stopping other add-on medication For inhaled treatments: consider decreasing after 3-6 months; continue at least moderate dose ICS Order of reduction based on risks and side-effects, cost and patient preference If good response to Type 2-targeted therapy Review the basics: differential diagsis, inhaler technique, adherence, comorbidities, side-effects, emotional support Consider high resolution chest CT (if t done) Reassess phetype and treatment options - Induced sputum (if available) - Consider add-on macrolide* - Consider add-on low dose OCS, but implement strategies to minimize side-effects - Consider bronchoscopy for alternative/additional diagses - Consider bronchial thermoplasty (+ registry) Stop ineffective add-on therapies Do t stop ICS For more details *Off-label 8 Continue to optimize management as in section 3, including: Notes: g pg 26 g pg Adolescents and adults with difficult-to-treat and severe asthma GINA Inhaler technique Adherence Comorbidity management Patients social/emotional needs Two-way communication with GP for ongoing care Adolescents and adults with difficult-to-treat and severe asthma GINA

10 IN DETAI Investigate and manage adult and adolescent patients with difficult-to-treat asthma Care by GP or SPECIAIST 1 Confirm the diagsis (asthma or differential diagses) Difficult-to-treat asthma is defined if the patient has persistent symptoms and/or exacerbations despite prescribing of GINA Step 4-5 treatment (e.g. medium or high dose ICS with ather controller such as ABA, or maintenance oral corticosteroids (OCS)). It does t mean a difficult patient. Consider referral to a specialist or severe asthma clinic at any stage, particularly if: There is difficulty confirming the diagsis of asthma Patient has frequent urgent healthcare utilization Patient needs frequent or maintenance OCS Occupational asthma is suspected Food allergy or anaphylaxis, as this increases the risk of death Symptoms are suggestive of infective or cardiac cause Symptoms are suggestive of complications such as bronchiectasis Presence of multiple comorbidities Are the symptoms due to asthma? Perform a careful history and physical examination to identify whether symptoms are typical of asthma, or are more likely due to an alternative diagsis or comorbidity. Investigate according to clinical suspicion. Dyspnea: COPD, obesity, cardiac disease, deconditioning Cough: inducible laryngeal obstruction (also called vocal cord dysfunction, VCD), upper airway cough syndrome (also called post-nasal drip), gastro-esophageal reflux disease (GERD), bronchiectasis, ACE inhibitors Wheeze: obesity, COPD, tracheobronchomalacia, VCD How can the diagsis of asthma be confirmed? Perform spirometry before and after bronchodilator to assess baseline lung function and seek objective evidence of variable expiratory airflow limitation. If initial reversibility testing is negative (<200m or <12% increase in FEV 1 ), consider repeating when symptomatic. If spirometry is rmal or is t available, provide the patient with a peak flow diary for assessing variability; consider bronchial provocation testing if patient is able to withhold bronchodilators (short-acting beta2-agonist (SABA) for >6 hours, ABA for up to 2 days depending on duration of action). See GINA 2018 for details about diagstic testing, and for other objective investigations. Airflow limitation may be persistent in patients with long-standing asthma, due to remodeling of the airway walls, or limited lung development in childhood. It is important to document lung function when the diagsis of asthma is first made. Specialist advice should be obtained if the history is suggestive of asthma but the diagsis cant be confirmed by spirometry. 2 ook for factors contributing to symptoms and exacerbations Systematically consider factors that may be contributing to uncontrolled symptoms or exacerbations, or poor quality of life, and that can be treated. The most important modifiable factors include: Incorrect inhaler technique (seen in up to 80% patients): ask the patient to show you how they use their inhaler; compare with a checklist or video Suboptimal adherence (up to 75% asthma patients): ask empathically about frequency of use (e.g. Many patients don t use their inhaler as prescribed. In the last 4 weeks, how many days a week have you been taking it t at all, 1 day a week, 2, 3 or more? or, Do you find it easier to remember your inhaler in the morning or the evening?. 8 Ask about barriers to medication use, including cost, and concerns about necessity or side-effects. Check dates on inhalers and view dispensing data, if available. Comorbidities: review history and examination for comorbidities that can contribute to respiratory symptoms, exacerbations, or poor quality of life. These include anxiety and depression, obesity, deconditioning, chronic rhisinusitis, inducible laryngeal obstruction (often referred to as VCD), GERD, COPD, obstructive sleep apnea, bronchiectasis, cardiac disease, and kyphosis due to osteoporosis. Investigate according to clinical suspicion. Modifiable risk factors and triggers: identify factors that increase the risk of exacerbations, e.g. smoking, environmental tobacco exposure, other environmental exposures at home or work including allergens (if sensitized), indoor and outdoor air pollution, molds and xious chemicals, and medications such as beta-blockers or n-steroid anti-inflammatory drugs (NSAIDs). For allergens, check for sensitization using skin prick testing or specific IgE. Regular or over-use of SABAs causes beta-receptor down-regulation and lack of response, 9 leading in turn to greater use. Overuse may also be habitual. Dispensing of 3 SABA canisters per year (average 1.5 puffs per day, or more) is associated with increased risk of ED visit or hospitalization independent of symptoms, 10 and dispensing of 12 canisters per year (one a month) increases the risk of death. 11 Risks are higher with nebulized SABA. continued 16 Adolescents and adults with difficult-to-treat and severe asthma GINA Adolescents and adults with difficult-to-treat and severe asthma GINA

11 Investigate and manage adult and adolescent patients with difficult-to-treat asthma cont d Anxiety, depression and social and ecomic problems: these are very common in patients with difficult asthma 4 and contribute to symptoms, impaired quality of life, and poor adherence Medication side-effects: systemic effects, particularly with frequent or continuous OCS, or long-term high dose ICS may contribute to poor quality of life and increase the likelihood of poor adherence. ocal side-effects of dysphonia or thrush may occur with high dose or potent ICS especially if inhaler technique is poor. Consider drug interactions including risk of adrenal suppression with use of P450 inhibitors such as itroconazole. 3 Review and optimize management Review and optimize treatment for asthma, and for comorbidities and risk factors identified in Section 2. For more details, see GINA 2018 Chapter 3. 8 Provide asthma self-management education, and confirm that patient has (and kws how to use) a personalized written or electronic asthma action plan. Refer to an asthma educator if available. Optimize inhaled controller medications: confirm that the inhaler is suitable for the patient; check and correct inhaler technique with a physical demonstration and teach-back method, check inhaler technique again at each visit. 12 Address intentional and unintentional barriers to adherence. 13 For patients with a history of exacerbations, switch to ICS-formoterol maintenance and reliever regimen if available, to reduce the risk of exacerbations. 14 Treat comorbidities and modifiable risk factors identified in Section 2, where there is evidence for benefit; however, there is evidence to support routine treatment of asymptomatic GERD. Avoid medications that make asthma worse (beta-blockers including eye-drops; aspirin and other NSAIDs in patients with aspirin-exacerbated respiratory disease). Refer for management of mental health problems if relevant. Consider n-pharmacologic add-on therapy, e.g. smoking cessation, physical exercise, healthy diet, weight loss, mucus clearance strategies, influenza vaccination, breathing exercises, allergen avoidance, if feasible, for patients who are sensitized and exposed. For details see GINA 2018 Box 3.9. Consider trial of n-biologic medication added to medium/high dose ICS, e.g. ABA, tiotropium, leukotriene modifier if t already tried (see Glossary) Consider trial of high dose ICS, if t currently used. 4 Review response after 3~6 months Schedule a review visit to assess the response to the above interventions. Timing of the review visit depends on clinical urgency and what changes to treatment have been made. When assessing the response to treatment, specifically review: Symptom control: symptom frequency, reliever use, night waking due to asthma, activity limitation Exacerbations since previous visit, and how they were managed Medication side-effects Inhaler technique and adherence ung function Patient satisfaction and concerns g Is asthma still uncontrolled, despite optimized therapy? YES: if asthma is still uncontrolled, the diagsis of severe asthma has been confirmed. If t done by w, refer the patient to a specialist or severe asthma clinic if possible. NO: if asthma is w well-controlled, consider stepping down treatment. Start by decreasing/ceasing OCS first (if used), then remove other add-on therapy, then decrease ICS dose (do t stop ICS). See GINA 2018 Box 3-7 for how to gradually down-titrate treatment intensity. g Does asthma become uncontrolled when treatment is stepped down? YES: if asthma symptoms become uncontrolled or an exacerbation occurs when high dose treatment is stepped down, the diagsis of severe asthma has been confirmed. Restore the patient's previous dose to regain good asthma control, and refer to a specialist or severe asthma clinic if possible, if t done already. NO: if symptoms and exacerbations remain well-controlled despite treatment being stepped down, the patient does t have severe asthma. Continue optimizing management. 18 Adolescents and adults with difficult-to-treat and severe asthma GINA Adolescents and adults with difficult-to-treat and severe asthma GINA

12 IN DETAI Assess and treat severe asthma phetypes Care by SPECIAIST, SEVERE ASTHMA CINIC IF AVAIABE 5 Assess the severe asthma phetype and other contributors Further assessment and management should be by a specialist, preferably in a multidisciplinary severe asthma clinic if available. The team may include a certified asthma educator and health professionals from fields such as speech pathology, ENT and mental health. Assessment includes: Assessment of the patient s inflammatory phetype: Type 2 or n-type 2? More detailed assessment of comorbidities and differential diagses Need for social/psychological support 4 Invite patient to enroll in a registry (if available) or clinical trial (if appropriate) What is Type 2 inflammation? Type 2 inflammation is found in ~50% of people with severe asthma. It is characterized by cytokines such as interleukin (I)-4, I-5 and I-13, which are often produced by the adaptive immune system on recognition of allergens. It may also be activated by viruses, bacteria and irritants that stimulate the innate immune system via production of I-33, although this pathway more typically leads to n-type 2 inflammation. Type 2 inflammation is often characterized by eosiphils, and may be accompanied by atopy, whereas n-type 2 inflammation is often characterized by neutrophils. 15 In many patients with asthma, Type 2 inflammation rapidly improves when ICS are taken regularly and correctly; this is classified as mild or moderate asthma. In severe asthma, Type 2 inflammation is relatively refractory to high dose ICS. It may respond to OCS but their serious adverse effects 3 mean that alternative treatments should be sought. Which patients are likely to have refractory Type 2 inflammation? The possibility of refractory Type 2 inflammation should be considered if any of the following are found while the patient is taking high-dose ICS: Blood eosiphils 150/μl, and/or FeNO 20ppb, and/or Sputum eosiphils 2%, and/or Asthma is clinically allergen-driven These criteria are suggested for initial assessment; the criteria for eligibility for Type 2-targeted biologic therapy may differ - see section 6b and local criteria. Consider repeating blood eosiphils and FeNO up to 3 times (e.g. when asthma worsens, before giving OCS), before assuming asthma is n-type 2. Since OCS rapidly reduce markers of Type 2 inflammation (blood eosiphilia, FeNO) in most patients, these tests should be performed before starting OCS (a short course, or maintenance treatment), or on the lowest possible OCS dose. 20 Adolescents and adults with difficult-to-treat and severe asthma GINA Why is the inflammatory phetype assessed on high dose ICS? Most RCT evidence about Type 2 targeted biologics is in such patients Currently, the high cost of biologic therapies generally precludes their widespread clinical use in patients whose symptoms or exacerbations and Type 2 biomarkers are found to respond to ICS when it is taken correctly Modifiable ICS treatment problems such as poor adherence and incorrect inhaler technique are common causes of uncontrolled Type 2 inflammation What other tests may be considered at the specialist level? Additional investigations may be appropriate for identifying less common comorbidities and differential diagses contributing to symptoms and/or exacerbations. Tests should be based on clinical suspicion, and may include: Blood tests: CBC, CRP, IgG, IgA, IgM, IgE, fungal precipitins including Aspergillus Allergy testing for clinically relevant allergens: skin prick test or specific IgE, if t already done Other pulmonary investigations: DCO; CXR or high resolution chest CT Other directed testing, e.g. ANCA, CT sinuses, BNP, echocardiogram Consider testing for parasitic infections, if Type 2 targeted biologic therapy is considered; this is because parasitic infection may be the cause of the blood eosiphilia, and because Type 2 targeted treatment in a patient with untreated parasitic infection could potentially lead to disseminated disease Consider need for social/psychological support Refer patients to support services, where available, to help them deal with the emotional, social and financial burden of asthma and its treatment, including during and after severe exacerbations. 4 Consider the need for psychological or psychiatric referral for patients with anxiety and/or depression. Involve multidisciplinary team care (if available) Multidisciplinary assessment and treatment of patients with severe asthma increases the identification of comorbidities, and improves outcomes. 16 Invite patient to enroll in a registry (if available) or clinical trial (if appropriate) Systematic collection of data will help in understanding the mechanisms and burden of severe asthma. There is an urgent need for pragmatic clinical trials in severe asthma, including active-controlled studies. Adolescents and adults with difficult-to-treat and severe asthma GINA

13 Assess and treat severe asthma phetypes cont d 6a If there is NO evidence of Type 2 inflammation If the patient has evidence of persistent Type 2 inflammation (section 5): Review the basics for factors that may be contributing to symptoms or exacerbations: differential diagsis, inhaler technique, adherence, comorbidities, medication side-effects (Section 2) Recommend avoidance of relevant exposures (tobacco smoke, pollution, allergens, irritants, infections). Ask about exposures at home and at work Consider additional diagstic investigations (if available and t already done): sputum induction to confirm inflammatory phetype, high resolution chest CT, bronchoscopy to exclude unusual comorbidities or alternative diagses such as tracheobronchomalacia or sub-glottic stesis Consider a trial of n-biologic add-on treatment if t already tried, e.g. tiotropium, leukotriene modifier, low-dose macrolide 17 (off-label; consider potential for antibiotic resistance). Consider add-on low dose OCS, but implement strategies such as alternate-day treatment to minimize side-effects. Stop ineffective add-on therapies. Consider bronchial thermoplasty, with registry enrollment. However, the evidence for efficacy and long-term safety is limited. 18,19 No biologic options are currently available for n-type 2 severe asthma. 6a Non-biologic options if there IS evidence of Type 2 inflammation For patients with elevated Type 2 biomarkers despite high dose ICS (see section 5), consider n-biologic options first, given the current high cost of biologic therapy: Assess adherence objectively by monitoring of dispensing records, blood prednisone levels, 20 or electronic inhaler monitoring. 21 In one study, suppression of high FeNO after 5 days of directly-observed therapy was an indicator of past poor adherence. 22 Consider clinical Type 2 phetypes for which specific add-on treatment is available (see GINA 2018 report Chapter 3D). For example, for aspirinexacerbated respiratory disease (AERD), consider add-on leukotriene modifier and possibly aspirin desensitization. For allergic bronchopulmonary aspergillosis (ABPA), consider add-on OCS ± anti-fungal agent. For chronic rhisinusitis and/or nasal polyposis, consider intensive intranasal corticosteroids; surgical advice may be needed. For patients with atopic dermatitis as well as severe asthma, consider add-on dupilumab (anti-i4-13). Consider increasing the ICS dose for 3-6 months, and review again 6b Consider add-on biologic Type 2 targeted treatments If available and affordable, consider an add-on Type 2 targeted biologic for patients with exacerbations and eosiphilic and/or allergic biomarkers despite taking high dose ICS-ABA with or without daily OCS. Where relevant, test for parasitic infection, and treat if present, before commencing Type 2 targeted treatment. Consider whether to start first with anti-ige or anti-i5/5r When choosing between available therapies, consider the following: Does the patient satisfy local payer eligibility criteria? Predictors of response (see below) Cost Dosing frequency Delivery route (SC or IV) Patient preference ocal payer eligibility criteria for biologic therapy may vary substantially; they are indicated here by the symbol. There is an urgent need for head-to-head comparisons of different biologics in patients eligible for more than one biologic. For any biologic therapy, ensure that the manufacturer s and/or regulator s instructions for storage, administration and the duration of monitoring postadministration are followed. Provide the patient with advice about what to do if they experience any adverse effects, including hypersensitivity reactions. g Add-on anti-ige for severe allergic asthma Currently approved: omalizumab for ages 6 years, given by SC injection every 2-4 weeks, with dose based on weight and serum IgE Mechanism: binds to Fc part of free IgE, preventing binding of IgE to FcƐR1 receptors, reducing free IgE and down-regulating receptor expression Eligibility criteria vary between payers, but usually include: Sensitization to inhaled allergen(s) on skin prick testing or specific IgE, and Total serum IgE and body weight within local dosing range, and More than a specified number of exacerbations within the last year Write your local eligibility criteria here: 22 Adolescents and adults with difficult-to-treat and severe asthma GINA Adolescents and adults with difficult-to-treat and severe asthma GINA

14 Assess and treat severe asthma phetypes cont d Benefits: RCTs in severe asthma: 34% decrease in severe exacerbations, 23 but significant difference in symptoms or quality of life. 24 In open-label studies in patients with severe allergic asthma and 1 severe exacerbation in last 12 months, there was a 50-65% reduction in exacerbation rate, 25, 26 a significant improvement in quality of life, 25 25, 26 and 40-50% reduction in OCS dose. Potential predictors of good response: Baseline IgE level does t predict likelihood of response 25 In RCTs: a greater decrease in exacerbations was observed (cf. placebo) if blood eosiphils 260/μl 27, 28 or FeNO 20ppb, 27 but in a large observational 26, 29 study, exacerbations were reduced with both low or high blood eosiphils Childhood-onset asthma Clinical history suggesting allergen-driven symptoms Adverse effects: injection site reactions; anaphylaxis in ~0.2% patients Suggested initial trial: at least 4 months g Add-on anti-i5 or anti-i5r for severe eosiphilic asthma Currently approved: For ages 12 years: mepolizumab (anti-i5), 100mg by SC injection 4-weekly, and benralizumab (anti-i5 receptor α), 30mg by SC injection every 4 weeks for 3 doses then every 8 weeks. For ages 18 years: reslizumab (anti-i5), 3mg/kg by IV infusion every 4 weeks. Mechanism: mepolizumab and reslizumab bind circulating I-5; benralizumab binds to I-5 receptor alpha subunit leading to lysis of eosiphils Eligibility criteria: these vary by product and between payers, but usually include: More than a specified number of severe exacerbations in the last year, and Blood eosiphils above specified level (e.g. 300/μl). In some cases there is a different eosiphil cutpoint for patients taking OCS. Write your local eligibility criteria here: Outcomes: RCTs in severe asthma patients with exacerbations in the last year, with varying eosiphil criteria: anti-i5 and anti-i5r led to ~55% reduction in severe exacerbations, improved quality of life, and small improvements in lung function and symptom control. 30 All reduced blood eosiphils, almost completely with benralizumab. 30 In patients taking OCS, OCS dose was able to be reduced by 40-60%. Potential predictors of good response: Higher blood eosiphils (strongly predictive) 31 Higher number of severe exacerbations in previous year (strongly predictive) 31 Adult-onset asthma 32 Nasal polyposis, maintenance OCS at baseline 33 Adverse effects: injection site reactions; anaphylaxis is rare; adverse events generally similar between active and placebo groups Suggested initial trial: at least 4 months g If there is good response to an initial trial of add-on Type 2 targeted therapy If the response is equivocal, consider extending the trial to 6-12 months If there is response, stop the biologic therapy Consider switching to a trial of a different Type 2 targeted therapy, if available and the patient is eligible; review response as above 24 Adolescents and adults with difficult-to-treat and severe asthma GINA Adolescents and adults with difficult-to-treat and severe asthma GINA

15 IN DETAI Manage and monitor severe asthma treatment Care by SPECIAIST and GP IN COABORATION 7 Review response and implications for treatment Review the patient s response to add-on biologic therapy after 3-4 months, and every 3-6 months for ongoing care, including: Symptom control and exacerbations Treatment intensity ung function Side-effects Affordability Patient satisfaction g If the patient has had a good response to Type 2 targeted therapy: Re-evaluate the need for each asthma medication (including the biologic) every 3-6 months, but do t completely stop ICS. Base the order of reduction or cessation of add-on treatments on patient risk factors, medication side-effects, cost, and patient satisfaction. For oral treatments, consider gradually decreasing or stopping OCS first, because of their significant adverse effects. Tapering may be supported by internet-based monitoring of symptom control and FeNO. 34 Monitor patients for risk of adrenal suppression, and provide patient and GP with advice about the need for extra corticosteroid doses during injury, illness or surgery for up to 6 months after cessation of long-term OCS. Continue to assess for presence of osteoporosis, and review need for preventative strategies including bisphosphonates. 35 For inhaled treatments, consider reducing the ICS dose after 3-6 months, but do t completely stop ICS. Current consensus advice is to continue at least medium dose ICS. For biologic treatments, current consensus advice is that a trial of withdrawal of the biologic may be considered if, after at least 12 months of treatment, asthma remains well-controlled on medium dose ICS therapy, and (for allergic asthma) there is further exposure to a previous well-documented allergic trigger. 36, 37 There are limited studies of cessation of biologic therapy. g If the patient has NOT had a good response to any Type 2 targeted therapy: Review the basics for factors contributing to symptoms, exacerbations and poor quality of life (see Section 2): diagsis, inhaler technique, adherence, modifiable risk factors and triggers including smoking and other environmental exposures at home or work, comorbidities, medication side-effects or drug interactions, socioecomic and mental health issues. Consider additional investigations (if t already done): high resolution chest CT; induced sputum to confirm inflammatory phetype, consider referral if available, including for diagsis of alternative conditions. Reassess treatment options (if t already done), such as add-on low-dose macrolide (off-label; consider potential for antibiotic resistance); consider addon low-dose maintenance OCS, but implement strategies such as alternateday therapy and add-on bisphosphonates 35 to minimize side-effects. Consider brochial thermoplasty (+ registry). Stop ineffective add-on therapies, but do t completely stop ICS 8 Continue to collaboratively optimize patient care Ongoing management of a patient with severe asthma involves a collaboration between the patient, the GP, specialist(s), and other health professionals, to optimize clinical outcomes and patient satisfaction. Continue to review the patient every 3-6 months including: Clinical asthma measures (symptom control; exacerbations; lung function) - see GINA 2018 report for details Comorbidities 16 The patient's risk factors for exacerbations Treatments (check inhaler technique and adherence; review need for add-on treatments; assess side-effects; optimize comorbidity management and npharmacologic strategies) The patient s social and emotional needs 4 The optimal frequency and location of review (GP or specialist) will depend on the patient s asthma control and risk factors and comorbidities,and their confidence in self-management, and may depend on local payer requirements and availability of specialist physicians. Communicate regularly about: Outcome of review visits (as above) Patient concerns Action plan for worsening asthma or other risks Changes to medications (asthma and n-asthma); potential side-effects Indications and contact details for expedited review 26 Adolescents and adults with difficult-to-treat and severe asthma GINA Adolescents and adults with difficult-to-treat and severe asthma GINA

16 Glossary of asthma medication classes For more details, see full GINA 2018 report and Appendix ( and Product Information from manufacturers. Medications Action and use Adverse effects Controller Medications Inhaled corticosteroids (ICS) (pmdis or DPIs) e.g. beclometasone, budesonide, ciclesonide, fluticasone propionate, fluticasone furoate, mometasone, triamcilone ICS are the most effective antiinflammatory medications for asthma. ICS reduce symptoms, increase lung function, improve quality of life, and reduce the risk of exacerbations and asthmarelated hospitalizations or death. ICS differ in their potency and bioavailability, but most of the benefit is seen at low doses (see GINA report Box 3-6 for low, medium and high doses of different ICS). Most patients using ICS do t experience side-effects. ocal side-effects include oropharyngeal candidiasis and dysphonia; these can be reduced by use of spacer with pmdis, and rinsing with water and spitting out after inhalation. ong-term high doses increase the risk of systemic side-effects such as osteoporosis, cataract and glaucoma. ICS and long-acting beta2-agonist bronchodilator combinations (ICS-ABA) (pmdis or DPIs) e.g. beclometasoneformoterol, budesonideformoterol, fluticasone furoate-vilanterol, fluticasone propionateformoterol, fluticasone propionate-salmeterol, and mometasoneformoterol. eukotriene modifiers (tablets) e.g. montelukast, pranlukast, zafirlukast, zileuton When a low dose of ICS alone fails to achieve good control of asthma, the addition of ABA to ICS improves symptoms, lung function and reduces exacerbations in more patients, more rapidly, than doubling the dose of ICS. Two regimens are available: low-dose combination beclometasone or budesonide with formoterol for maintenance and reliever treatment; and low-dose maintenance ICS-ABA with SABA as reliever. Target one part of the inflammatory pathway in asthma. Used as an option for controller therapy, particularly in children. Used alone, they are less effective than low dose ICS; when added to ICS, they are less effective than ICS-ABA. The ABA component may be associated with tachycardia, headache or cramps. ABA should t be used without ICS in asthma due to increased risk of serious adverse outcomes. Few side-effects in placebo-controlled studies except elevated liver function tests with zileuton and zafirlukast. 28 Adolescents and adults with difficult-to-treat and severe asthma GINA Medications Action and use Adverse effects Chromones (pmdis or DPIs) e.g. sodium cromoglycate and nedocromil sodium Add-on Controller Medications ong-acting anticholinergic (tiotropium, mist inhaler, 6 years) Anti-IgE (omalizumab, SC, 6 years) Anti-I5/anti-I5R (anti-i5 mepolizumab [SC, 12 or 6 years ], reslizumab [IV, 18 years] or anti-i5 receptor benralizumab [SC, 12 years] Systemic corticosteroids (tablets, suspension or IM or IV injection) e.g. prednisone, prednisolone, methylprednisolone, hydrocortisone Very limited role in long-term treatment of asthma. Weak antiinflammatory effect, less effective than low-dose ICS. Require meticulous inhaler maintenance. Add-on option at Step 4 or 5 by mist inhaler for patients with a history of exacerbations despite ICS ± ABA An add-on option for patients with severe allergic asthma uncontrolled on high dose ICS- ABA Add-on options for patients with severe eosiphilic asthma uncontrolled on high dose ICS- ABA Short-term treatment (usually 5 7 days in adults) is important in the treatment of severe acute exacerbations, with main effects seen after 4 6 hours. Oral corticosteroid (OCS) therapy is preferred to IM or IV therapy and is as effective in preventing relapse. Tapering is required if treatment is given for more than 2 weeks. ong-term treatment with OCS may be required for some patients with severe asthma, but sideeffects are problematic Side effects are uncommon but include cough on inhalation and pharyngeal discomfort. Side-effects are uncommon but include dry mouth. Reactions at the site of injection are common but mir. Anaphylaxis is rare. Headache, and reactions at injection site are common but mir. Short-term use: some adverse effects e.g. sleep disturbance, GERD, appetite increase, hyperglycaemia, mood changes. ong-term use: limited by significant systemic adverse effects e.g. cataract, glaucoma, hypertension, diabetes, adrenal suppression, osteoporosis. Assess for OCS risk and treat appropriately. Adolescents and adults with difficult-to-treat and severe asthma GINA